Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease.

INTRODUCTION: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD. METHODS: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing. RESULTS: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant. CONCLUSIONS: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation.

Off-label use of Lumen-apposing metal stents for treatment of short benign biliary strictures.

BACKGROUND: Endoscopic stenting is the mainstay of treatment for benign biliary strictures. There is a not-negligible rate of recurrence and stent migration. Lumen-apposing metal stents (LAMS) have a unique design with short length, large diameter and wide flanges which make them less prone to migration. AIMS: To describe the intraluminal use of LAMS to treat short benign biliary strictures. METHODS: All consecutive patients who underwent bi-flanged LAMS placement for benign biliary strictures, in approximately 6 years, were retrospectively included. Primary outcomes were technical and clinical success; secondary outcomes were number of endoscopic procedures, adverse events evaluation and stricture recurrence during follow-up. RESULTS: Seventy patients (35 male, mean age 67) were enrolled; bilio-enteric anastomotic stricture was the most common etiology. Technical and clinical success were 100 % and 85.7 %, respectively. Patients with post-surgical stricture had a higher success rate than patients with non-surgical stricture or with bilio-enteric anastomotic stricture (90.4 %, 86.3 % and 81.4 %, respectively). Adverse events were 12/70 (17.1 %): stent migration was the most frequent (8/70, 11.4 %). Stricture recurrence was found in 10/54 patients (18.5 %). CONCLUSION: LAMS placement could be safe and effective treatment for short benign biliary strictures in patients in which a significant caliber disproportion between stricture and the duct above was revealed.

Recurrence rate and management after endoscopic papillectomy in a tertiary referral center.

BACKGROUND AND STUDY AIMS: Endoscopic papillectomy (EP) is considered a safe procedure for ampullary lesions. Few data are available on management of residual and recurrent adenomas. The aims of the present study were to evaluate long-term recurrence rate, median time-to-recurrence after EP and treatment of both residual and recurrent adenomas. PATIENTS AND METHODS: Consecutive patients who underwent EP of major and minor papilla at our endoscopy center between 2011 and 2022 were enrolled. Residual adenoma was defined as the endoscopic evidence of adenomatous tissue after EP. Recurrent adenoma was defined as the presence of adenomatous tissue after the first endoscopic follow-up and complete adenoma resection. RESULTS: 95 patients satisfied the inclusion criteria. Pathology after resection showed adenoma with low-grade dysplasia (LGD) in 52 patients, high-grade dysplasia (HGD) in 25 patients, adenocarcinoma in 6 patients, NET in 4 patients and not-neoplastic duodenal mucosa in 8 patients. Adverse events occurred in 25 % of patients. The median follow-up after EP was 22.5 months. Local residual was observed in 27 patients (28,4 %) and recurrence after the endoscopic retreatments occurred in 11 patients (11,6 %). Furthermore, recurrence occurred in 16 of 68 patients with adenoma-free after a first endoscopic follow-up and 9 patients developed at least a second recurrence. All the recurrences but one were endoscopically treated. CONCLUSIONS: EP and its ancillary treatments for residual and recurrent adenomas is an effective treatment for ampullary tumors. Long-term surveillance demonstrates that recurrences can be mainly treated endoscopically.

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

BACKGROUND: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization. CASES: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described. CONCLUSIONS: This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

Deep brain stimulation of globus pallidus internus and subthalamic nucleus in Parkinson's disease: a multicenter, retrospective study of efficacy and safety.

BACKGROUND: Deep brain stimulation (DBS) is an established therapeutic option in advanced Parkinson's disease (PD). Literature data and recent guidelines remain inconclusive about the best choice as a target between the subthalamic nucleus (STN) and the globus pallidus internus (GPi). MATERIALS AND METHODS: We retrospectively reviewed the clinical efficacy outcomes of 48 DBS-implanted patients (33 STN-DBS and 15 GPi-DBS) at a short- (<1 year from the surgery) and long-term (2-5 years) follow-up. Also, clinical safety outcomes, including postoperative surgical complications and severe side effects, were collected. RESULTS: We found no difference between STN-DBS and GPi-DBS in improving motor symptoms at short-term evaluation. However, STN-DBS achieved a more prominent reduction in oral therapy (L-DOPA equivalent daily dose, P = .02). By contrast, GPi-DBS was superior in ameliorating motor fluctuations and dyskinesia (MDS-UPDRS IV, P < .001) as well as motor experiences of daily living (MDS-UPDRS II, P = .03). The greater efficacy of GPi-DBS on motor fluctuations and experiences of daily living was also present at the long-term follow-up. We observed five serious adverse events, including two suicides, all among STN-DBS patients. CONCLUSION: Both STN-DBS and GPi-DBS are effective in improving motor symptoms severity and complications, but GPi-DBS has a greater impact on motor fluctuations and motor experiences of daily living. These results suggest that the two targets should be considered equivalent in motor efficacy, with GPi-DBS as a valuable option in patients with prominent motor complications. The occurrence of suicides in STN-treated patients claims further attention in target selection.

Rapidly progressive multiple system atrophy in a patient carrying LRRK2 G2019S mutation.

BACKGROUND: Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. CASE: We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. CONCLUSIONS: LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes.

Endoscopic entero-enteral bypass to treat postsurgical benign complications of hepatico-jejunostomy: Update of a 7-year single-center experience.

Background and study aims Since 2014, we have been using a new endoscopic approach to improve management of biliary adverse events (BAEs) after bilio-digestive anastomosis. We provide an update about our experience at 7 years. Patients and methods Patients with BAEs on hepatico-jejunostomy underwent entero-enteral endoscopic by-pass (EEEB) creation between the duodenal/gastric wall and the biliary jejunal loop. Evaluation of results during our seven-year experience was performed. Results Eighty consecutive patients (32 patients from Jan 2014 to Dec 2017 and 48 patients from Jan 2018 to Jan 2021) underwent EEEB, which was successful in all but one patient. The cumulative AEs rate was 32 %. Endoscopic retrograde cholangiography (ERC) through the EEEB successfully treated all types of BAEs in these patients. Cumulative disease recurrence was 3.8 % (three patients) and was retreated through the EEEB. Conclusions The update of our experience with EEEB confirmed that in patients with BAEs after bilio-digestive anastomosis, EEEB allows successful long-term treatment of different BAEs in a tertiary referral center with an acceptable rate of related AEs.

The clinical and genetic spectrum of primary familial brain calcification.

Primary familial brain calcification (PFBC), formerly known as Fahr's disease, is a rare neurodegenerative disease characterized by bilateral progressive calcification of the microvessels of the basal ganglia and other cerebral and cerebellar structures. PFBC is thought to be due to an altered function of the Neurovascular Unit (NVU), where abnormal calcium-phosphorus metabolism, functional and microanatomical alterations of pericytes and mitochondrial alterations cause a dysfunction of the blood-brain barrier (BBB) and the generation of an osteogenic environment with surrounding astrocyte activation and progressive neurodegeneration. Seven causative genes have been discovered so far, of which four with dominant (SLC20A2, PDGFB, PDGFRB, XPR1) and three with recessive inheritance (MYORG, JAM2, CMPK2). Clinical presentation ranges from asymptomatic subjects to movement disorders, cognitive decline and psychiatric disturbances alone or in various combinations. Radiological patterns of calcium deposition are similar in all known genetic forms, but central pontine calcification and cerebellar atrophy are highly suggestive of MYORG mutations and extensive cortical calcification has been associated with JAM2 mutations. Currently, no disease-modifying drugs or calcium-chelating agents are available and only symptomatic treatments can be offered.

Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants.

Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.

Flavonoid Intake in Relation to Colorectal Cancer Risk and Blood Bacterial DNA.

Flavonoids have been inversely associated to colorectal cancer (CRC) and are plausible intermediaries for the relation among gut microbiome, intestinal permeability and CRC. We analyzed the relation of flavonoid intake with CRC and blood bacterial DNA. We conducted a case-control study in Italy involving 100 incident CRC cases and 200 controls. A valid and reproducible food-frequency questionnaire was used to assess dietary habits and to estimate six flavonoid subclass intakes. We applied qPCR and 16S rRNA gene profiling to assess blood bacterial DNA. We used multiple logistic regression to derive odds ratios (ORs) of CRC and Mann-Whitney and chi--square tests to evaluate abundance and prevalence of operational taxonomic units (OTUs) according to flavonoid intakes. Inverse associations with CRC were found for anthocyanidins (OR for the highest versus the lowest tertile = 0.24, 95% confidence interval, CI = 0.11-0.52) and flavanones (OR = 0.18, 95% CI = 0.08-0.42). We found different abundance and prevalence according to anthocyanidin and flavanone intake for OTUs referring to Oligoflexales order, Diplorickettsiaceae family, Staphylococcus, Brevundimonas, Pelomonas and Escherischia-Shigella genera, and Flavobacterium and Legionella species. The study provides evidence to a protective effect of dietary anthocyanidins and flavanones on CRC and suggests an influence of flavonoids on blood bacterial DNA, possibly through intestinal permeability changes.

Antiphospholipid-Related Chorea: Two Case Reports and Role of Metabolic Imaging.

Background: Antiphospholipid syndrome (APS) is a complex acquired autoimmune disease with a wide clinical spectrum. Chorea is a rare neurological manifestation of APS. Cases: We report two elderly patients with APS-related chorea in whom functional imaging (18F-FDG positron emission tomography, FDG-PET) supported the diagnosis and compare our findings with existing literature. Literature Review: Among 142 clinical cases of antiphospholipid-related chorea found in literature, only 10 had undergone brain metabolic imaging. Striatal hypermetabolism was evident in all cases (6) that underwent FDG-PET cerebral imaging. Cerebral perfusion single photon emission computed tomography (SPECT) was normal in two cases, while the other two presented with basal ganglia hypoperfusion. Conclusions: Brain FDG-PET usually shows striatal hypometabolism in neurodegenerative types of chorea as opposed to striatal hypermetabolism observed in most cases of chorea from reversible etiologies, such as APS-related chorea. When a patient's clinical presentation is not clearly suggestive of either a neurodegenerative or autoimmune chorea, and first-line investigations are normal, FDG-PET may help in the differential diagnosis, especially in the presence of striatal hypermetabolism. SPECT data are less numerous and show either normal scans or basal ganglia hypoperfusion.

Non-intubated general anesthesia in prone position for advanced biliopancreatic therapeutic endoscopy: A single tertiary referral center experience.

Background and Study Aim: Advance biliopancreatic endoscopies are nowadays performed in non-operating room anesthesia (NORA) under general anesthesia (GA). We evaluate the outcomes of non-intubated patients in prone position who received GA for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) in a tertiary referral center for digestive endoscopy. Patients and Methods: Anesthesiological records, anamnestic, and intraoperative data of patients who underwent advanced therapeutic biliopancreatic endoscopies at our tertiary referral center from January 2019 until January 2020 were collected in the present observational study. Results: One hundred fifty-three patients (93 M; median age: 68-year-old; mean ASA status: 2) were considered eligible for a procedure in the prone position with GA in spontaneous breathing. Prone position was always the initial setting. Propofol administration through a target-controlled infusion (TCI) pump was the choice to achieve GA. In our experience, desaturation appears to be the most frequent adverse event, accounting for 35% of cases (55/153). Treatment foresaw additional oxygen through a nasopharyngeal catheter, which proved to be a sufficient measure in almost all patients (52/55). Other adverse events (i.e., inadequate sedative plan, pain, and bradycardia) accounted for 2.6% of cases (4/153). Conclusions: Non-intubated GA in the prone position may be regarded as a safe procedure, as long as the anesthesiological criteria of exclusion are respected and the anesthesiological team has become acquainted with the peculiar NORA setting and familiar with the management of possible adverse events.

Blood Bacterial DNA Load and Profiling Differ in Colorectal Cancer Patients Compared to Tumor-Free Controls.

Inflammation and immunity are linked to intestinal adenoma (IA) and colorectal cancer (CRC) development. The gut microbiota is associated with CRC risk. Epithelial barrier dysfunction can occur, possibly leading to increased intestinal permeability in CRC patients. We conducted a case-control study including 100 incident histologically confirmed CRC cases, and 100 IA and 100 healthy subjects, matched to cases by center, sex and age. We performed 16S rRNA gene analysis of blood and applied conditional logistic regression. Further analyses were based on negative binomial distribution normalization and Random Forest algorithm. We found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls. For high levels of gene copies, community diversity was higher in colon cancer cases than controls. Bacterial taxa and operational taxonomic unit abundances were different between groups and were able to predict CRC with an accuracy of 0.70. Our data support the hypothesis of a higher passage of bacteria from gastrointestinal tract to bloodstream in colon cancer. This result can be applied on non-invasive diagnostic tests for colon cancer control.